Role of transforming growth factor-α in von Hippel- Lindau (VHL)~-/- clear cell renal carcinoma cell proliferation: A possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis

摘要

Mutations of the VHL tumor Suppressor gene occur in patients with VHL disease and in the majority of sporadic clear cell renal carci- nomas (VHL~-/- RCC). Loss of VHL protein function is associated with constitutive expression of mRNAs encoding hypoxia-induc- ible proteins, such as vascular endothelial growth factor. Overpro- duction of angiogenic factors might explain why VHL~-/- RCC tumors are so highly vascularized, but whether this overproduction is sufficient for oncogenesis still remains unknown. In this report, we examined the activity of transforming growth factor-α (TGF- α), another VHL-regulated growth factor. We show that TGF-α mRNA and protein are hypoxia-inducible in VHL~-/- RCC cells expressing reintroduced VHL. In addition to its overexpression by VHL~-/- RCC cells, TGF-α can also act as a specific growth-stimulatory factor for VHL~-/- RCC cells expressing reintroduced wild-type VHL, as well as primary renal proximal tubule epithelial cells, the likely site of origin of RCC. This role is in contrast to those of other growth factors overexpressed by VHL~-/- RCC cells, such as vascular endo- thelial growth factor and TGF-β1, which do not stimulate RCC cell proliferation. A TGF-α-specific antisense oligodeoxynucleotide blocked TGF-α production in VHL~-/- RCC cells, which led to the dependence of those cells on exogenous growth factors to sustain growth in culture. Growth of VHL~-/- RCC cells was also signifi- cantly reduced by a drug that specifically inhibits the epidermal growth factor receptor, the receptor through which TGF-α stimu- lates proliferation. These results suggest that the generation of a TGF-α autocrine loop as a consequence of VHL inactivation in renal proximal tubule epithelial cells may provide the uncontrolled growth stimulus necessary for the initiation of tumorigenesis.